The sodium-activated K+ current (IKNa) is present in many neurons of the mammalian brain. Using wave- clamp experiments we will test the hypothesis that IKNa is a significant but overlooked delayed outward current responsible for action potential repolarization throughout the brain. Our preliminary results suggest that IKNa is by far the largest K+ current in action potential repolarization in mitral cells. The importance of IKNa in controlling excitability and repolarizing action potentials in the nervous system has been overlooked because the sodium channel blocker TTX is often used to study K+ currents in neurons; we found that TTX blocks the component of INaP that activates IKNa. Thus TTX blocks IKNa as a secondary consequence of its blocking INaP. We recently showed that IKNa was functionally coupled to one or more persistent sodium currents, (INaP). Hence, another aim of this proposal is to attempt to reveal the molecular identity of the one or more channels producing INaP which is functionally coupled to IKNa. Although INaP is thought to be the product of voltage gated sodium channels (VGSCs), the exact identity of the individual VGSC alpha and beta subunits which produce INaP in particular neuron types, has not been well established. INaP, is the major target of most antiepileptic drugs. In neocortex, the prominent INaP in layer V pyramidal neurons, augments excitability in neurons that comprise the neocortical output circuits which are involved in the spread of epileptic activity. Thus, revealing the molecular identify of INaP in layer 5 pyramidal neurons might lead to drugs that more specifically and effectively target INaP leading to better control of epilepsy. We will also evaluae the role of IKNa in that cell type and others to reveal the extent to which the interaction of IKNa and INap is important in regulating excitability. These studies may also provide a better understanding of other neurological diseases where increased activity of INaP may be a factor such as Amyotrophic Lateral Sclerosis and Familial Hemiplegic Migraine; additionally, blockade of INaP may be a useful treatment for Multiple Sclerosis. Specific Aims are: 1. to attempt to determine the molecular identities of TTX-sensitive INaP in several neuronal types including layer 5 cortical pyramidal neurons; 2. to attempt to identify the INaP component(s) functionally linked to the sodium-activated potassium channel (IKNa); 3. to test the hypothesis that IKNa is a significant but overlooked factor in action potential repolarization in many neuronal types.